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The Major Opiates

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... recognized British traded for tea with Chinese 1773 Brits control of India-begin to supply opium to China basis for Opium wars between China & British China ... – PowerPoint PPT presentation

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Title: The Major Opiates


1
The Major Opiates
  • Most common used drug for relief of pain
  • Only true Narcotics (stupor, sleep, analgesia)
  • compare to marijuana and cocaine which have other
    effects such as euphoria, stimulant properties.
  • Also cough suppressant antidiarrea properties
  • Narcotics is Greek word for stupor
  • not for illicit psychoactive drug

2
The Major Opiates
  • Opium derived from juice of poppy plant
  • What is an opiate?
  • Analgesic
  • Acts on endorphan/enkephalin receptors
  • Antagonized by naloxone
  • Most potent painkiller, but severe dependence

3
The Major Opiates
  • Endogenous Opiods
  • Endorphine, Enkephalin, Dynorphin
  • in pituitary
  • in pain sensors (spinal cord midbrain)
  • affective states (amygdala, hippocampus, locus
    coeruleus, and cerebral cortex)
  • autonomic system (e.g. medulla)
  • stomach and intestines

4
Classification of Opiates
  • 3 specific groups of opiates used
  • Natural Narcotics
  • Opium extracts (morphine, codeine thebaine)
  • Semisynthetic Narcotics
  • Slight changes to chemical composition of
    morphine
  • E.g. heroin
  • Synthetic Narcotics
  • Not related to morphine, but produce opiate like
    responses

5
Classification of Opiates
  • Opium, morphine, heroin, thebaine codeine
    referred to as opiates
  • Synthetic Narcotics referred to a synthetic
    opiates or synthetic opiate-like drugs

6
History of Opium
  • Native to Middle East in areas bordering
    Mediterranean
  • Also Laos, Thailand, Afghanistan, Mexico
    Columbia
  • Use dates back 6000 years to Summarians
  • Egyptians used it medically 3500 years ago
  • Excavation of ceramic opium pipe in Cypres
  • Common use among Islamic peoples for medical
    recreational purposes
  • not forbidden in Koran as were alcohol many
    other drugs

7
History of Opium
  • Arab traders took to India China
  • Also, western Europe learned about it from Arabs
    during crusades
  • 1520 Paracelsus laudanum
  • 1680 Thomas Sydenham his version of laudanum
  • Next 200 yrs primary consumption of opium is as
    drink

8
China Opium
  • Up to 1700s Chinese use limited to painkiller
  • 18th century development of opium smoking
  • China first laws against Opium use in 1729
  • dependence problem recognized
  • British traded for tea with Chinese
  • 1773 Brits control of India-begin to supply opium
    to China
  • basis for Opium wars between China British

9
China Opium
  • China tried to control drug problem
  • 1839 Defiance of European power
  • Confiscation of large quantities of opium
  • Burned it in Canton
  • Start of opium war

10
Opium Wars
  • First War
  • 1839-1842 Hong Kong ceded to British (til 1997),
    Canton Shanghai opened for trade
  • Second War
  • 1858-1860 British joined by French American
    forces
  • 20 mill. pounds sterling, opening of remaining
    ports, legalization regulation of opium trade
    (ended 1906)

11
Difference in Opium Use
  • Major difference between opium use in China
    West was method of consumption
  • laudanum
  • Identified with Victorian Era
  • Opening of respectable parlors
  • Chinese smoked it
  • Identified with Opium Dens
  • Ideal of lazy Chinese
  • Seen as degrading dirty vice

12
Opium the West
  • Western societies
  • Used opium as aspirin
  • Cheaper than liquor
  • No negative public opinion
  • No real problem with cops
  • Used to sooth infants children
  • Teething, colic or to keep them quite
  • Women used it more than male
  • Greater addiction

13
Problems in the West
  • Collision of cultures
  • Chinese building railroad
  • 1875 San Francisco outlawed opium dens opium
    smoking
  • Laws targeted not at opium (laudanum legal), but
    at Chinese
  • Federal laws prohibiting opium smoking followed

14
Morphine the West
  • 1803 Sertürner separated morphine from opium
  • Increased dependence potential
  • Morphine 10 X opium potency
  • Morpheus Greek God of dreams
  • 1856 development of hypodermic needle
  • Use became widespread
  • Doctors began injecting opium solutions (thought
    sidestep addiction-thought purer safer )
  • Used during Civil War for injuries (dependency
    known as soldiers disease)

15
Heroin From Bad to Worst
  • In 1874 British chemist altered morphine
  • but unnoticed until rediscovered in 1898
  • 1898 German Heinrich Dreser
  • Heroin-altered form of morphine
  • 3X-4 X more potent than morphine
  • Thought to be safer than morphine
  • Sold by Bayer beginning in lieu of codeine as
    medicine for coughs, bronchitis, tuberculosis
  • Heroin also began to replace morphine in addicted
    individuals

16
Opiates in the US
  • By 1900 250, 000 opium dependent people in US
  • By 1913, 400,000 lbs of opium imported into U.S.
    for consumption by U.S. population of 90 mill.
    people
  • Laws began cropping up around this time and
    formed the cornerstone of American drug laws
    today

17
Opiates in US Early 1900s
  • Harrison Act of 1914
  • No ban on opiates, but doctors had to register
    with IRS
  • Decreased prescriptions
  • Users not seen as victims but weak
  • heroin drug of choice in black market
  • Shift of users not women, but white urban adult
    males

18
Opiates Use in 1960s
  • 3 Major Social Developments
  • Crackdown cause shortage of heroin increased
    smuggling price
  • Increased levels of crime
  • Increased used by urban minorities
  • Peace movement, hippies drug culture
  • Vietnam War

19
Opiates Use in 1980, 90s
  • Golden Triangle
  • Laos, Burma Thailand
  • Afghanistan, Pakistan, Iran Mexico
  • Dominate heroin supply route
  • Shift from Turkey as main supplier
  • Opened a large vacuum
  • Fentanyl China White used as surgical
    anesthetic prescription painkiller
  • 10 to 10,000 X stronger than heroin
  • Sometimes found itself on black market

20
Opiates in 20th century US
  • Morphine is schedule II
  • Heroin schedule I
  • In Britain comparably seems as Schedule II
  • Schedule I no accepted medical use
  • Schedule V has medical use, not too addictive
  • most legally used opioids are either
    semisynthetic or synthetic
  • no legal U.S. use for heroin - purely illicit
    drug (in the US) with large worldwide market
    today

21
Opiates in 20th century US
  • about 4-5000 metric tons opium produced in 1990
    (2,200 lbs)
  • compared to 200-225,000 metric tons coca in same
    year

22
Business of Opiates
  • opium grown in 2 primary regions of world using
    simple farming techniques
  • poppies grown, petals fall, small incisions,
    liquid oozes out - opium
  • opium - 10 morphine 0.5 codeine
  • morphine refined in growing areas then
    transported or processed
  • heroin - equal amount - then diluted to 1-10

23
Business of Opiates
  • extremely profitable as a business
  • kg morphine in Italy 12,500 - heroin in U.S. 1.7
    million
  • 10 kg opium 300 in production region
  • heroin in New Delhi 10,000
  • in U.S. 1.5 million

24
Absorption, Distribution, Metabolism Excretion
  • Most opiates poorly absorbed through GI tract
    (except codeine)
  • Effective nasally and through lungs
  • Opium frequently smoked, heroin snorted
  • Most effective i.v. (heroin 100 times more potent
    i.v. than orally)

25
Absorption, distribution excretion
  • In bloodstream distributed throughout body
  • accumulating in kidney, lung, liver, spleen,
    muscle brain
  • Opiates and blood brain barrier
  • Morphine does not cross BBB well
  • only 20 of circulating enters brain
  • 30-60 min to reach significant brain
    concentrations

26
Absorption, distribution excretion
  • Heroin more lipid soluble so penetrates BBB
    better
  • Both morphine heroin cross placenta
  • heroin converted to morphine once it cross the
    BBB
  • once crossed BBB codeine 10 converted to morphine

27
Absorption, distribution excretion
  • Most opiates rapidly metabolized in liver and
    excreted by kidney
  • Half-life about 2.5-3 hrs
  • Duration of effect 4-5 hrs
  • 5-15 mg optimal analgesic dose for morphine -
    addicts 2 g H

28
Opiates
  • Opium, morphine, codeine
  • Derivatives or semisynthetic (minor modification
    in structure)
  • heroin, nalorphine, and hydromorphone
  • Synthesizedhave different structures, but
    similar properties
  • Meperidine (Demerol)
  • Fentanyl (Sublimaze)
  • Proxyphene (Darvon, Darvocet) lousy analgesic
  • Methadone (Dolophine)

29
Absorption, distribution excretion
  • Have somewhat different pharmacological effects
  • Differ in potency, duration of action oral
    effectiveness
  • Because of differences in pharmacokinetics
  • Heroin more potent than morphine when injected,
    but same when taken orally.
  • slight modification of heroin from morphine
    allows it to cross BBB betterWhat would this do?

30
Absorption, distribution excretion
  • Metabolized into morphine in brain
  • because it gets there quicker, more rapid intense
    effects.
  • Codeine- 12x less potent that morphine when
    injected
  • better absorbed orally (morphine\heroin weak
    alkaloids)
  • Endogenous opiates more potent than heroin
  • But inactivated quickly
  • Fentanyl-50 times more powerful than heroin (IM)
  • Used for surgery, but easy for addicts to OD

31
Medical Use
  • analgesia
  • sedation-markedly differs between individuals
  • poor sedative in general
  • anti-diarrhea agents
  • extremely effective for dysentery (1800's)
  • were the only effective agents in that time

32
Mechanism of Action
  • act via the endogenous opiate system
  • 1960's discovery of the opiate antagonist
    naloxone (Narcan7)
  • implication of common receptor site for opiates
    actions
  • 1973 Pert and Snyder discovery of "opiate
    receptors"
  • led to discovery of several endorphins in 1975
  • beta-endorphin
  • enkephalin
  • dynorphin

33
Pharmacological Actions
  • Primary effect of narcotics is sedative-hypnotic
  • Some cause stimulation immediate after injection
  • Cats and some humans are the only mammals that
    show stimulation

34
Pharmacological Actions
  • Primary sites of action - CNS and GI tract
  • For both medicine and abuse, opiate use due to 3
    actions
  • Analgesia (best for dull continuous, not sharp)
  • still feel sensations, can remain alert
  • vision, hearing, touch okay
  • Euphoria (dream like state with intense visions)
  • Constipation (used for diarrhea and dysentery)

35
Pharmacological Actions
  • Natural pain relief system
  • Used for chronic, not sharp, acute pains
  • childbirth, battlefield injuries, strenuous
    exercise, acupuncture
  • addiction to exercise related to endorphin
    release
  • can you be addicted to an endogenous substance?

36
Pharmacological Actions
  • Opiates also relieve psychological pain
  • anxieties, feelings of inadequacy, hostility
    aggression
  • produce extremely pleasant mood states - euphoria
  • pain relief due to central effect - no effect on
    sensory nerve transmission
  • begins at spinal cord continues throughout CNS

37
Abuse Potential
  • Abuse is related to euphoriant actions (CNS
    action)
  • 2 main groupings
  • visual illusions-dream like states
  • clarity of thought and alleviation of
    psychological pain

38
Abuse Potential
  • Trance-like state - visual illusions
  • dream-like images - great deal of clarity
  • doesn't influence sensory input
  • the only perceptual effect is on pain
  • can alleviate physical pain
  • can alleviate psychological pain
  • strong emotionally pleasant feelings

39
Side Effects
  • vomiting
  • very common with first dose
  • chance-may be due to effect on the vestibular
    apparatus
  • respiratory depression
  • decrease sensitivity to CO2
  • occurs at low doses-those common for analgesia
  • increase dose-increase depression
  • most common cause of death in overdose

40
Side Effects
  • Body temperature
  • resetting of body temperature thermostat
  • with limited use-lowers temperature by about 1
    degree
  • can persist for a months
  • Sex hormones
  • inhibited
  • males-decreased testosterone levels-decreased sex
    drive
  • females-decreased estrogen

41
Side Effects
  • Cardiovascular effects
  • increased skin blood flow-gives them a warm
    feeling
  • blood pressure decrease upon standing -faint
  • Pinpoint pupils
  • signs of overdose
  • seizures
  • Catatonia (only at very high doses)

42
RECEPTOR TYPES MEDIATING OPIOID EFFECTS
  • m1
  • spinal supraspinal analgesia
  • m2
  • respiratory depression
  • GI motility
  • nausea
  • euphoria
  • physical dependence (withdrawal symptoms)
  • pupillary contraction

43
RECEPTOR TYPES MEDIATING OPIOID EFFECTS
  • k (kappa)
  • spinal supraspinal analgesia
  • sedation
  • pupil contraction
  • dysphoria, psychotomimetic
  • d (delta)
  • spinal supraspinal analgesia
  • positive reinforcing effects
  • modulate activity of m receptors

44
Receptor Location
  • m receptors - pain modulating regions of brain
  • dorsal horn of spinal cord
  • brain stem
  • PAG
  • thalamus
  • hypothalamus
  • striatum

45
Receptor Location
  • k receptors - broad distribution
  • deep layers of cerebral cortex
  • limbic system
  • hypothalamus
  • d receptors - emotional response regions of brain
  • limbic system (amygdala)
  • frontal cortex
  • nucleus accumbens

46
Receptor Location
  • opioid induced euphoria not well understood
  • seems to involve m2 receptors also d
  • definitely not k
  • opioids act as modulators and inhibit release of
    excitatory amino acid neurotransmitters
  • all act via second messenger systems
  • found on presynaptic nerve terminals
  • also found to serve as cotransmitters (released
    with NE

47
Tolerance Dependence
  • develop with repeated use
  • More rapidly and to greater degree as potency
    increases
  • Heroin methadone develop different patterns for
    withdrawal
  • Heroin withdrawal begins 4-5 hrs after last dose
  • strong flu like symptoms
  • greatest magnitude of symptoms between 24-72 hrs
  • pretty much done in a couple of weeks

48
Tolerance Dependence
  • Methadone withdrawal 24-48 hrs after last dose
  • withdrawal symptoms reported to be less intense
  • however, much greater duration
  • can take months to clear all withdrawal symptoms
  • Methadone admin subcu for analgesia
  • Same potency as morphine, half potency as heroin
  • More effective orally than both
  • Suppresses opiate withdrawals
  • actions 3 to 4 time longer than morphine

49
Tolerance Dependence
  • Why do we pay for people to be maintained on
    methadone?
  • 1) effective orally - limits needle use
  • 2) long duration action
  • 3) effective dose remains stable
  • 4) cheap
  • 5) does not produce euphoria as well
  • actually blocks to heroin
  • 6) prevents opiate withdrawal

50
Treatment
  • Therapeutic groups (Synanon Daylop)
  • In West Berlin- 15 abstained compared to 4
  • Elimin of cond craving (to drug related stim)
    through extinction class cond
  • Mostly blocking narcotic effects
  • Antagonist break up drug taking from
    reinforcement
  • Naloxone (Narcan7)-not too effective
  • Naltrexen (Trexen7 or ReVia7) block up to 3 days
  • What may be a problem with antagonist?

51
Treatment
  • Substituting narcotics w/less disruptive
    (Methadone)
  • Developed by Nazis in WWII
  • Dole and Nyswander (1976)narcotic addicitions
  • Gave large levels of methadone
  • Despite addiction went back to school, got jobs
    etc.,

52
Treatment
  • Withdrawal symptoms in addicts with naloxone
    admin
  • Administer both heroin naloxone repeatedly
    together
  • no tolerance or dependence develops
  • interesting way to see what receptor type
    mediates what responses
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